Genetic Disorders & DSD

Genetic Disorders & Differences of Sex Development

Differences of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or anatomic sex is atypical. Categories include sex chromosome DSDs (e.g., Klinefelter syndrome 47,XXY; Turner syndrome 45,X), 46,XY DSD (e.g., androgen insensitivity, 5-alpha-reductase deficiency), and 46,XX DSD (e.g., congenital adrenal hyperplasia).

Inheritance Patterns — Quick Reference

Klinefelter Syndrome (47,XXY)

• Most common sex chromosome aneuploidy in males (~1 in 500-1,000 live male births)
• Etiology: meiotic nondisjunction producing an extra X chromosome
• Clinical: tall stature, long extremities, small firm testes, gynecomastia, sparse body/facial hair, infertility (azoospermia), low testosterone with elevated LH/FSH (hypergonadotropic hypogonadism), learning/behavioral difficulties
• Diagnosis: karyotype (47,XXY); hormonal panel (decreased testosterone, elevated LH, FSH, estradiol)
• Management: testosterone replacement starting in adolescence; fertility counseling (sperm extraction/ICSI may be possible); treat gynecomastia, osteoporosis risk, metabolic syndrome; multidisciplinary support

Reference: AMBOSS — Differences (disorders) of sex development

Down Syndrome (Trisomy 21)

• Most common autosomal aneuploidy and leading genetic cause of intellectual disability (~1 in 700 live births); incidence increases with advanced maternal age
• Etiology: meiotic nondisjunction (~95%), Robertsonian translocation (~4%), or mosaicism (~1%)
• Clinical: intellectual disability, characteristic facies (upslanting palpebral fissures, epicanthal folds, flat nasal bridge, small ears), single transverse palmar crease, hypotonia, short stature, brachycephaly
• Associated conditions: congenital heart defects (endocardial cushion/AV septal defect most characteristic), duodenal atresia, Hirschsprung disease, hypothyroidism, atlantoaxial instability, early-onset Alzheimer disease, increased risk of ALL/AML
• Prenatal screening: first-trimester combined (nuchal translucency, PAPP-A, beta-hCG); cell-free fetal DNA (cfDNA); quad screen (elevated hCG, elevated inhibin A, decreased AFP, decreased estriol); confirmatory: CVS or amniocentesis (karyotype)
• Management: multidisciplinary — early intervention, routine screening for cardiac, thyroid, hearing/vision, cervical spine, and hematologic issues

Reference: AMBOSS — Down syndrome

Fragile X Syndrome

• Most common inherited cause of intellectual disability; second most common genetic cause overall (after Down syndrome)
• Etiology: X-linked; CGG trinucleotide repeat expansion in the FMR1 gene leading to hypermethylation and silencing of FMRP. Full mutation: over 200 repeats; premutation: 55-200 repeats
• Clinical (males more severely affected): intellectual disability, long narrow face, large protruding ears, prominent jaw, macroorchidism (post-puberty), hyperextensible joints, mitral valve prolapse; behavioral — autism spectrum features, ADHD, anxiety
• Premutation carriers: fragile X-associated tremor/ataxia syndrome (FXTAS) in older males; primary ovarian insufficiency (FXPOI) in females
• Diagnosis: molecular testing for CGG repeat number and methylation status of FMR1
• Management: supportive — behavioral/educational interventions, speech and occupational therapy, treatment of comorbid ADHD, anxiety, seizures

Reference: AMBOSS — Fragile X syndrome

Turner Syndrome (45,X)

• Monosomy X (or partial loss/mosaicism) in a phenotypic female; ~1 in 2,500 live female births
• Clinical: short stature (most common feature), webbed neck, low posterior hairline, shield chest with widely spaced nipples, cubitus valgus, lymphedema of hands/feet in infancy, streak ovaries leading to primary amenorrhea and infertility, delayed/absent puberty
• Associated conditions: bicuspid aortic valve and coarctation of the aorta (cardiac screening essential), horseshoe kidney, autoimmune thyroiditis, osteoporosis, hearing loss
• Diagnosis: karyotype (45,X or mosaic 45,X/46,XX); elevated FSH/LH with decreased estrogen (hypergonadotropic hypogonadism)
• Management: growth hormone therapy in childhood; estrogen replacement at pubertal age for secondary sexual development and bone health; cardiac imaging (echo/MRI); monitor for thyroid, renal, and hearing issues

Reference: AMBOSS — Turner syndrome

Marfan Syndrome

• Autosomal dominant — FBN1 gene mutation (fibrillin-1 protein), chromosome 15; ~25% de novo mutations
• Clinical: tall stature, long limbs, arachnodactyly, pectus excavatum/carinatum, scoliosis, high arched palate, ectopia lentis (upward lens dislocation), aortic root dilation leading to dissection/rupture (most life-threatening feature), MVP, spontaneous pneumothorax
• Diagnosis: Ghent nosology criteria (major + minor criteria across systems); echocardiogram at diagnosis
• Management: beta-blockers (atenolol) or losartan to slow aortic dilation; annual echo; ophthalmology; avoid contact sports; genetic counseling; prophylactic aortic root replacement when indicated

Neurofibromatosis Type 1 (NF1)

• Autosomal dominant — NF1 gene (neurofibromin tumor suppressor), chromosome 17; ~50% de novo mutations; most common single-gene disorder (1:3,000)
• Diagnosis requires 2 of 7 criteria: 6 or more cafe-au-lait macules (over 5mm prepubertal / over 15mm postpubertal), 2 or more neurofibromas or 1 plexiform neurofibroma, axillary/inguinal freckling (Crowe sign), optic glioma, Lisch nodules (iris hamartomas — pathognomonic), sphenoid dysplasia or tibial pseudarthrosis, first-degree relative with NF1
• Complications: learning disabilities (~50% — most common complication), ADHD, scoliosis, short stature, plexiform neurofibromas leading to MPNST, optic pathway glioma, increased risk of leukemia (JMML), hypertension (renal artery stenosis or pheochromocytoma)
• Management: annual neurological exam, BP, ophthalmology, developmental assessment; MEK inhibitor (selumetinib) FDA-approved for plexiform neurofibromas in children

Prader-Willi Syndrome

• Paternal deletion of 15q11-q13 (70%), maternal uniparental disomy (25%), or imprinting defect; contrast with Angelman syndrome (maternal 15q11 deletion)
• Biphasic presentation: Phase 1 (infancy) — profound hypotonia, poor suck, feeding difficulties, undescended testes, almond-shaped eyes; Phase 2 (toddler/childhood) — hyperphagia, rapid obesity, short stature, mild-moderate intellectual disability, behavioral issues (temper tantrums, OCD features, skin-picking)
• Associated: obesity leading to T2DM, sleep apnea, scoliosis; GH deficiency; hypogonadism; hypothyroidism; high pain threshold
• Diagnosis: methylation analysis (detects all 3 mechanisms)
• Management: growth hormone therapy (start early, even in infancy); strict dietary and caloric control with supervised food access; early intervention PT/OT/speech; behavioral management; sleep study for OSA

Master Comparison — Genetic Syndromes